This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Formula display:

Abstract

Background

As the number of proton therapy centers increases, so does the need for studies which
compare proton treatments between institutions and with photon therapy. However, results
of such studies are highly dependent on target volume definition and treatment planning
techniques. Thus, standardized methods of treatment planning are needed, particularly
for proton treatment planning, in which special consideration is paid to the depth
and sharp distal fall-off of the proton distribution. This study presents and evaluates
a standardized method of proton treatment planning for craniospinal irradiation (CSI).

Methods

We applied our institution’s planning methodology for proton CSI, at the time of the
study, to an anatomically diverse population of 18 pediatric patients. We evaluated
our dosimetric results for the population as a whole and for the two subgroups having
two different age-specific target volumes using the minimum, maximum, and mean dose
values in 10 organs (i.e., the spinal cord, brain, eyes, lenses, esophagus, lungs,
kidneys, thyroid, heart, and liver). We also report isodose distributions and dose-volume
histograms (DVH) for 2 representative patients. Additionally we report population-averaged
DVHs for various organs.

Results

The planning methodology here describes various techniques used to achieve normal
tissue sparing. In particular, we found pronounced dose reductions in three radiosensitive
organs (i.e., eyes, esophagus, and thyroid) which were identified for optimization.
Mean doses to the thyroid, eyes, and esophagus were 0.2%, 69% and 0.2%, respectively,
of the prescribed dose. In four organs not specifically identified for optimization
(i.e., lungs, liver, kidneys, and heart) we found that organs lateral to the treatment
field (lungs and kidneys) received relatively low mean doses (less than 8% of the
prescribed dose), whereas the heart and liver, organs distal to the treatment field,
received less than 1% of the prescribed dose.

Conclusions

This study described and evaluated a standardized method for proton treatment planning
for CSI. Overall, the standardized planning methodology yielded consistently high
quality treatment plans and perhaps most importantly, it did so for an anatomically
diverse patient population.

Keywords:

Proton; Craniospinal irradiation; CSI; Medulloblastoma

Background

The number of cancer centers that offer proton therapy as a treatment option is rising.
Within the last 10 years, the number of proton centers worldwide has almost doubled;
from 22 in 2003 to 38 in 2012. The rate of increase has been even more pronounced
in the United States: in 2003, there were 3 active centers in the U.S., and currently
there are 10 active centers, with 6 more scheduled to open within the next 2 years.
As a result, there is increased interest in comparing treatment efficacies and toxicities
from proton therapy to those of photon therapy [1-3]. This is especially true for children, [4-6] for whom survival rates are high, making proton therapy’s potential for sparing normal
tissues particularly relevant. Particular attention has been paid to craniospinal
irradiation (CSI) in pediatric patients [7-10] because: (1) CSI is a standard component in the treatment for medulloblastoma, the
second most common solid tumor in children [11-13]; (2) the potential to reduce dose anterior to the spine with proton CSI could lead
to reduced toxicity in organs such as the thyroid, heart, and lungs [13,14]; and (3) still-developing normal tissues in children are highly radiosensitive [15]. As a result, treatments that irradiate large portions of the body, such as CSI,
are of particular concern.

Until recently, the limited number of proton centers in operation has limited the
amount of patient-outcomes data available for review, especially for pediatric patients.
As a result, comparisons between proton and photon treatments have typically been
performed using indirect comparisons using case studies or nonrandomized groups [2,16]. Additionally, many previous studies have been criticized for focusing on improvements
in proton therapy (i.e., comparing outcomes between different proton techniques) rather
than comparisons between proton and photon therapies [1,3,16-19]. Thus, although the existing studies provide valuable insight, there is a definitive
need for studies that rigorously compare the risks and benefits of using proton and
photon irradiation in clinical settings. Because the results of such studies are highly
dependent on the target volume definition and treatment planning techniques, standardized,
i.e., documented and reproducible, methods of proton and photon treatment planning
are needed to reliably perform these comparisons across a population of patients.
Treatment planning for photon CSI is well understood and thoroughly described in the
literature [20-22]. Conversely, a comprehensive description of treatment planning for proton CSI does
not exist in the literature.

The objective of this study was to describe and evaluate a standardized method for
proton treatment planning for CSI. We present a detailed methodological description
of the planning techniques used at our institution, at the time of this study, for
proton CSI. Then, we describe application of this methodology to a sample population
of 18 pediatric patients. Finally, we compared dosimetric properties of the treatment
plans resulting from the methodology to determine whether the methodology yields consistently
high quality plans.

Methods

Facility-specific technical information

To better enable comparison between the treatment techniques described here and those
used by other institutions, we briefly review the technical features our treatment
system, i.e., The University of Texas M.D. Anderson Cancer Center Proton Therapy Center
Houston (MDACC-PTCH), that are of relevance to passively scattered proton CSI. The
proton treatment system (Probeat, Hitachi America Limited, Inc, Tarrytown, USA) consists
of a synchrotron (70–250 MeV) and a beam transport system that bifurcates into six
treatment stations. The CSI treatments described in this work were planned for rotating
gantries with passive-scattering nozzles; we have two such gantries at our institution,
allowing patients to be easily switched between treatment rooms. Specifically the
nozzle includes a rotating range modulator wheel, a binary stack of range shifters,
a contoured and compensated double scattering system, beam monitoring instrumentation,
collimators, and a range compensator. This treatment equipment can produce beam energies
(defined at the nozzle entrance) of 100, 120, 140, 160, 180, 200, 225, and 250 MeV,
spread-out-Bragg-peaks ranging in size from 2 to 16 g/cm2, and field sizes of up to 25 x 25 cm2. The dose rate depends on the scatterer (small, medium, or large) that is in place.
CSI fields are commonly treated with a large scatterer and have a dose rate of approximately
1 Gray (Gy) min per minute at isocenter. The layout, capabilities, and performance
characteristics of the treatment equipment were previously described in detail in
the literature [23,24].

The various modes proton beam operation (treatment, physics, and service) is managed
by an overall control system. In addition, there is an independent safety control
system. Data management is handled by the oncology information system (MOSAIQ, IMPAC
Medical Systems Inc Sunnyvale, CA) [24]. For proton treatment planning, we use a commercial treatment planning system (TPS)
(Eclipse version 8.9, Varian Medical Systems, Palo Alto, CA). Dose calculations are
performed with a proton pencil beam algorithm [25] on a 2.5-mm isotropic dose calculation grid.

The patient treatment couch (in the treatment room described above) is a computer
controlled robotic system with three orthogonal axes of translation (vertical, longitudinal,
and lateral) and three orthogonal rotational axes (pitch, roll, and yaw). Because
of the large size of the gantry and its pit, the couch base is mounted outside of
the gantry and the couch top is mounted to the couch base in a cantilevered configuration.
The couch top extension, the portion of the couch top in contact with the patient,
is predominantly made of a carbon fiber composite material that was specially selected
for its strength, uniform transparency to the beams of kilovoltage photons used for
radiographic patient positioning and alignment, and uniform and minimal perturbation
of proton treatment beams.

General plan overview

The beam arrangements for proton CSI include two opposed lateral oblique cranial fields
and postero-anterior spinal field(s). For standard-risk medulloblastoma patients,
we prescribe 23.4 Gy (RBE [relative biological effectiveness]) (i.e., 21.3 Gy × 1.1
RBE). The units of Gy (RBE) are assigned in accordance with our clinic’s standard
of care and the recommendations of ICRU Report 78, [26] which assumes proton beams have a higher RBE than photon beams. The fractionation
schedule is 1.8 Gy per fraction for 13 fractions with 3 junction shifts. Typically,
junction shifts are 1–2 cm apart, depending on spine length. The general clinical
guidelines used for proton CSI included the following: (1) coverage of the cerebrospinal
fluid (CSF) by the 100% isodose to lower end of the thecal sac (S2 or S3); (2) good
coverage of the anterior skull base; (3) as much coverage as possible to the cribriform
plate, balanced with planning criteria that the 100% isodose does not intercept the
eyes; (4) maximum isodose line intercepting the thyroid should be 5% or less (isodose
lines visually evaluated slice by slice); (5) no overshoot into the esophagus; and
(6) a homogeneous dose across the the spinal cord without excessive hot or cold spots
(> 105% of the prescribed dose or < 95% of the prescribed dose).

Patient immobilization and imaging

The immobilization technique used at our institution for proton CSI is described below;
it has, in our experience, led to reproducible set-ups. Patients undergo computer
tomography (CT) simulation in the supine position on a (10 cm thick) polystyrene foam
slab (Associated Foam Plastics, Houston, USA) that is inserted between the patient
and the table top. The foam slab is a rigid hard plate and does not conform to the
patient. This slab elevates the patient so that oblique cranial fields do not pass
through the treatment couch. Additionally, the patient’s head is immobilized with
a thermoplastic mask (WFR/Aquaplast Corp. and Qfix Systems, LLC, Avondale, USA) and
plastic head holder (Medtech, CIVCO, Orange City, USA) to optimize the neck curvature
for patient sedation needs and cranial field placement. A photograph and a sagittal
CT image of the patient set-up and immobilization are show in Figures 1 and 2, respectively.

Figure 1.Photograph of a patient in the set-up position for proton CSI.

Figure 2.Sagittal CT image showing the patient set-up and immobilization for representative
patient (patient 10: male, age 9). The window and level of the image was adjusted to visualize the digitally inserted
couch top extension (the portion of the couch that is in contact with the patient),
foam pad, thermoplastic mask, and plastic head holder. Isocenters for the cranial
field(s), upper spine filed, and lower spine field are indicated with blue × and labeled 1, 2, and 3 respectively.

After the patients are immobilized, CT images are acquired using a multi-slice CT
scanner (General Electric LightSpeed RT16, GE Healthcare, Waukesha, USA). CT images
are acquired with a 2.5-mm slice thickness in an area that extends approximately 2–3 cm
superior to the patient’s thermoplastic mask holder to approximately 3–4 cm inferior
to the patient's sacrum. Additionally, the entire thickness of any object with potential
to be in the beam path is included in the scan. Intravenous contrast agents are not
used in CT imaging for CSI planning because currently available agents do not enhance
our ability to delineate the CSF target. In addition, use of such agents would artificially
increase the Hounsfield units (HU) values, which could result in overshoot of the
proton beams, i.e., irradiation of tissue distal to the craniospinal axis [27].

Image processing and contours

Before the CT scan is imported into the TPS, it is post processed to delete the portion
of the image containing the CT couch top extension (the portion of the couch that
is in contact with the patient, Figure 2) and to insert a digital representation of the extension in its place. Inserting
a treatment couch top that mimics the physical dimensions and materials of the actual
treatment couch top is important because the accuracy of the delivered proton beam
range requires accurate knowledge of the materials through which the beam passes during
the planning process. The digital couch used at our institution was described elsewhere
[28] and a similar digital couch was reported for treatment planning at the proton facility
in Korea [29].

Similar to conventional photon therapy, target volume contours in proton therapy are
used to define the lateral shape of the treatment field (i.e., block definition).
However, unlike their photon counterparts, contours for targets and critical structures
in proton treatments are used by the TPS to automatically select beam range in the
patient and the width of the spread-out Bragg peak (SOBP) so that it covers the target
in the direction of the beam axis. To insure that the TPS correctly assigns these
machine parameters, the HU are manually reassigned for any contours that include high
density objects or imaging artifacts. Surgical clips or screws, and catheters are
examples where HU are re-assigned for CSI treatment planning; such manual corrections
were required for about one-third of the patients included in this study. These manual
heterogeneity corrections are particularly important for spinal treatment fields that
are oriented in the posterior-anterior direction, with the spinal target in the posterior
aspect of the patient and most normal tissues at risk are either anterior or lateral
to it. Heterogeneity correction methods for proton treatment planning were described
in detail elsewhere [30].

For all proton CSI patients, the CTV contour includes the entire CSF space (including
the brain, and spinal canal through the cauda equina to the level of the S2/S3 vertebral
junction [Figure 3b]). However, to account for some of the age-specific considerations of designing
spinal treatment fields, we define the anterior edge of the target volume in the spine
in two ways (Figures 3a, b). For patients who have not reached skeletal maturity as determined by bone age,
(typically those younger than 15 years of age), the target volume includes the spinal
canal and an additional normal tissue target volume (NTTV), which includes the entire
vertebral bodies. As we described in a recent study [31], the rationale for this “is to avoid sharp dose gradients in the vertebral bodies
in patients whose skeletons are still maturing. More specifically, proton treatments
that are designed to irradiate only the spinal canal have high dose gradients distal
to the spinal canal and lead to non-uniform irradiation of the vertebral bodies. Uniformly
irradiating a larger target volume that fully encompasses the vertebral bodies is
thought to reduce the risk of asymmetric growth of the vertebral body in patients
whose skeletons are still maturing, [7,32], i.e., those under the age of 15 years.” For patients older than 15 years, the spinal
portion of the CTV includes only the spinal canal and extends no more than 2–3 mm
into the vertebral bodies, reducing the dose to bone marrow which may allow for better
tolerance of the chemotherapy that is required.

Figure 3.Age-specific target volumes for two patients. (a) Target volume for a 4-year-old patient included the spinal canal and the entire
vertebral body, and (b) target volume for a 15-year-old patient included only the spinal canal. Both volumes
also included the brain.

Field-specific details

Cranial fields in pediatric proton CSI are initially defined by a target volume that
includes the brain contour and portions of the upper spine contour. The cranial fields
are typically angled 15 degrees from the horizontal plane to reduce dose to the lens
and improve dosimetric coverage of the cribiform plate. Collimators are generally
not rotated, and a sufficient air gap (approximately 12–15 cm) is provided to avoid
collisions of the nozzle and couch top. When designing the cranial fields, the inferior
field edges are typically designed first. They extend to the patient’s shoulders to
allow for feathering of the cranial-spinal field junctions, i.e., the edges of the
cranial fields in the remaining junction-shifted plans are approximately 1 cm and
2 cm superior to the shoulders. The remaining field edges are defined superiorly by
adding approximately 2.5 cm to the superior aspect of the brain contour (for flash),
and laterally by extending the brain contour inferiorly to the shoulders with a 2.5 cm
margin on the patient’s neck and editing the anterior neck contour off the oral pharynx
and mandible as much as possible. Additionally, the right and left cranial fields
are individually edited so that their respective field edges approximately bisect
the right and left ocular globes, do not include either lens, and maintain as much
coverage of the cribriform plate as possible.

The spinal fields are initially defined by the CTV and margins that include allowances
for uncertainties in the depth and lateral directions. The number of spinal fields
varies on the basis of spine length. In all cases, the superior border of the uppermost
spinal field is matched to the inferior border of the cranial fields. Then, depending
on the length of the spine, a second spinal field is matched to the inferior border
of the upper spinal field, and if needed, a third spinal field is matched to the inferior
border of the second spinal field. Lateral field edges are defined using a 1-cm margin
around the spinal target volume. Typical field borders for a representative adolescent
patient are shown in Figure 4.

Cranial and spinal field isocenters are selected during treatment planning and are
defined to simplify patient setup. The field isocenters for the cranial fields are
placed at the patients’ midline such that they are, at minimum, 3 cm from the field
edges, i.e., 3 cm from the internal edges of the cranial blocks. The field isocenter
for each spinal field is located at the same x coordinate (left-right axis) as the
cranial fields. The isocenter’s y coordinate (anterior-posterior axis) is fixed for
all spinal fields but differs from that of the cranial fields; it is set in the polystyrene
foam pad posterior to the patient such that the couch height in the room is high enough
to reduce collision issues. The z (superior-inferior axis) coordinate differs for
each spinal field and is placed midway between each field’s superior and inferior
borders. Typical field isocenters for a representative adolescent patient are shown in Figures 2 and 4.

Uncertainty margins

Uncertainty margins are designed for each treatment field to ensure coverage of age
specific target volumes (described in the following section). Uncertainty margins
are calculated for each treatment field using a methodology similar to that used in
our previous studies [30,33] and following the methods originally outlined by Moyers and Miller [34] and Moyers et al. [35]. The distal uncertainty margin (DM) is determined using.

(1)

where 3.5% of Cd, the water-equivalent depth (cm) to the distal edge of a field’s target contour,
is used to account for uncertainties in the CT number and the conversion of the electron
densities to proton relative linear stopping powers. The 0.3 cm is added to account
for range uncertainty due to variations in accelerator energy, material thickness
in the scattering system, and compensator density.

The proximal uncertainty margin, PM, is determined using

(2)

where Cp is the water-equivalent depth (cm) to the proximal edge of the field’s target contour.
The lateral uncertainty margin, LM, is determined using

(3)

where IM represents the margin for internal motion (cm), SM represents setup uncertainty (cm), and P represents the 50%–90% penumbral width (cm). Thus, the value of LM defines the lateral expansion of the field-specific apertures beyond the cranial
and spinal target volumes. According to our standard of care, IM is taken to be 0 cm and SM 0.3 cm. For the spinal fields, this typically results in an LM value of 1 cm. LM is also considered for the cranial fields, but it serves as a baseline on which flash
is added to the superior aspect of the treatment fields.

Although the uncertainty margins for the cranial and spinal fields are determined
using the same equations, there are some differences in how the margins are implemented.
For the cranial fields, PM and DM values are applied as planning parameters. That is, the TPS selects the beam range,
modulation, and energy based on the requirement that the prescribed dose is delivered
to the cranial target and its margins. Conversely, because there is a one-to-one correspondence
between each spinal target and spinal field, values of PM and DM are incorporated into the spinal targets, which expands the target region proximal
and distal to the spinal canal. This approach streamlines the optimization process
because it provides visualization of the uncertainty margins relative to the dose
distribution. As a result, edits for optimization can be made judiciously.

Once the uncertainty margins are determined, the following equation based on the works
of Moyers et al. [35] and Urie et al. [36] is applied. This equation defines the amount of expansion or smearing of the range
compensator. The equation effectively decreases the range compensator thickness such
that proton penetration depth in the patient is increased in order to maintain distal
coverage in the presence of radiological path length variations due to internal anatomical
motion; note that this correction is variable across the compensator and is not a
single fixed value. It is defined using

(4)

where S is the amount of smear determined using the quantities IM, SM, and 3% of the Cd. S is calculated for the spinal fields only. Most cranial fields are not designed to
have range compensators because even in the case of maximum smear, the milling structure
of the compensator does not match the curvature or thickness gradients of the patients’
skulls. Note that our comment rereading not using range compensators for most brain
fields specifically refers to the type of cranial fields which are intended to cover
the whole brain; range compensators are used when planning boost fields (not discussed
in this study) because the field is specifically conformed to cover a particular gross
target volume rather than the entire brain).

Optimization of dose distributions

After the initial fields are optimized and calculated, the dose distributions are
reviewed, and we begin the process of field-specific optimization. That is, each field
is individually optimized to provide uniform coverage of target volumes and meet constraints
on dose to normal tissues. Typically, optimization begins with the cranial fields.
Cranial field optimization is done in several steps. First, the general shape of the
23.4 Gy (RBE) isodose line is reviewed to ensure that it includes the cerebrospinal
fluid in the subarachnoid space. Ideally, this means that the 23.4 Gy (RBE) isodose
line extends minimally to the interior edge of the skull and maximally 1–2 mm outside
the exterior edge of the skull. If needed, adjustments to the general shape of the
23.4 Gy (RBE) isodose line are made through changes to the proximal and distal margins
of the cranial fields. Then, to improve dosimetric homogeneity within the cranial
target region, we edit the plan’s dose normalization value by selecting an initial
normalization value to create uniform coverage of the cranial target region by the
23.4 Gy (RBE) isodose line. The normalization is finely adjusted to reduce the higher
dose values or hot spots (at least 24.6 Gy (RBE)) that would result from scatter in
immobilization devices and variations in skull thickness. At this point, if they were
being used, range compensators would be manually edited to attenuate dose to the cochlea
and smoothed (further smeared) to reduce their impact on dosimetric inhomogeneity
in the brain. For plans prescribed to 23.4 Gy (RBE), most compensators are removed
to reduce the number of hot and cold streaks (> 105% of the prescribed dose or < 95%
of the prescribed dose) in the cranial dose distributions. For plans prescribed to
36 Gy (RBE), use of range compensators to reduce dose to the cochlea is evaluated
on a case-by-case basis.

Next, the spinal fields are optimized for uniform coverage of the 23.4 Gy (RBE) isodose
line relative to the age-specific spinal target. This process begins with the uppermost
spinal field and ends with the lowest spinal field and involves several steps. First,
the general shape of the 23.4 Gy (RBE) isodose line is assessed relative to the age-specific
spinal target. Ideally, the distal edge of the 23.4 Gy (RBE) isodose line coincides
with the distal edge of the spinal target, and the proximal edge of the 23.4 Gy (RBE)
isodose line coincides with the proximal edge of the spinal target or, maximally,
just anterior to the dorsal skin surface. If needed, the general shape of the 23.4 Gy
(RBE) isodose line is adjusted relative to the spinal target by making small changes
to the proximal and distal margins of the spinal fields. Second, to improve dosimetric
uniformity within the spinal target region, the weight of the spinal field is adjusted
relative to the plan normalization value. In general, spinal field weights can differ
from their initial setting of 1.0 by ±0.5% to ±5%, and in most cases, the largest
weight is assigned to the field incident upon the sacrum. Third, field-specific range
compensators are edited to reduce hot and cold spots in the dose distribution. These
edits differ slightly for each field because of differences in anatomy. In the upper
spinal field, edits are made to reduce hot and cold spots due to scatter from the
head holder or changes in the neck curvature (e.g., interfraction variation in neck
flexion). Additionally, compensator thickness is increased in the thyroid region to
block isodose lines that are greater than 5% of the prescribed dose from crossing
the medial edge of the thyroid contour. In the spinal field incident to the sacrum,
edits are made to increase compensator thickness on the basis of the patient’s sacral
curvature. In all cases, field-specific edits to the compensators are made and then
smoothed (i.e., applied a smoothing function to remove any abrupt steps in compensator
topography which can occur when a compensator is manually edited) to ensure that small
shifts in the patient setup do not compromise dosimetric coverage of the spinal canal.

After, the spinal fields are optimized for uniform dosimetric coverage of the age-specific
spinal target, attention is focused on reducing dose inhomogeneities at the field
junctions. The junction region is defined as the region where the edges of the cranial/spinal
and spinal/spinal fields align: 2–3 CT slices in the superior direction and 2–3 CT
slices in the inferior direction. This region is 1.25-1.50 cm in length, is contained
laterally and distally within the spinal target and is shifted on a weekly basis.
In the junction region, hot spots are defined by isodose lines greater than 108% of
the prescribed dose, and cold spots are defined by isodose lines less than 95% of
the prescribed dose. Hot spots and cold spots are removed using three procedures:
edits to the apertures forming the field junction, fine edits to the field weights,
and edits to the abutting fields' compensators. Edits to the apertures are made so
that the field edges will be precisely aligned to one another. Once the fields are
precisely aligned, the field weights are finely adjusted to balance coverage of the
spinal canal with the 100% isodose line and reductions in the dose at the field junctions.
After the field weights are optimized, remaining regions of isodose lines greater
than 110% of the prescribed dose may indicate fine adjustments to the field apertures
are needed to improve field alignment. After that, the field compensators are edited,
if needed. These edits are designed to reduce hot spots in the spinal canal by removing
steep gradients within the compensator and shifting hot spots from the spinal canal
to the vertebral body.

Finally, to assess the combined effects of the optimization processes, the display
of cranial and spinal target volumes are turned off, and the location of the 100%
isodose line relative to the interior border of the skull and spinal canal is evaluated
for each of the three junction-shifted plans. If needed, final edits to the isodose
coverage are made by scaling the 100% isodose line in an individual plan, but because
this final edit scales the dose distribution for all treatment fields in an individual
plan, it is rarely used. Once all three junction-shifted plans individually meet the
planning criteria, they are combined and re-evaluated as a summed plan. Then, based
on the dosimetric evaluation of the summed plan, final edits to the individual junction-shifted
plans are performed, if needed, until the summed plan meets all objectives and constraints.

Patient population

To evaluate the quality of our treatment planning methodology, we applied the methodology
to an anatomically diverse and representative population of patients. Eighteen pediatric
patients (ages 2 to 16 years of age) were selected using the consecutive sampling
method [37]. The inclusion criteria were male and female patients between 2 and 18 years of age
at the time of treatment who received proton CSI between 2006 and 2009 at the UTMDACC-PTCH.
Patients who received photon therapy or who were not simulated in the supine position
were excluded. The sample was fairly evenly distributed in age and sex. The patients
varied with respect to anatomical stature, age, and the corresponding volumes of their
internal organs (Table 1). For each patient the same planning process was employed.

Table 1.Patient demographics including volumes of organs of interest, for which each organ
was contoured in its entirety*

Evaluation of planning methodology

For each patient the treatment plans were evaluated to assure adherence with our clinical
guidelines by reviewing the isodose distributions (on each axial CT slice) and dose
volume histograms (DVH) for the ten organs of interest (lungs, liver, heart, kidneys,
spinal cord, brain, eyes, lenses, esophagus, and thyroid). Two representative patients
(indices 10 and 13) were selected for presentation in the results section of this
manuscript. Patient 10 (age 9) is representative of the younger patients planned with
the larger age-specific target volume that included CSF and vertebral bodies. Patient
13 (age 16) is representative of the older patients planned with the smaller age specific
target volume that included only CSF. Both patients were of average stature and their
organ volumes were within the corresponding one standard deviation of the mean organ
volumes of the population.

After evaluation of individual patient isodose distributions and DVHs, we completed
population-based dosimetric and statistical analyses. First, average DVHs were generated
for ten organs of interest by calculating the average values of D5% to D100% (in 5% increments) and maximum dose (Dmax). Next, for the same ten organs, average values for minimum dose (Dmin), Dmax, were calculated separately for the entire population of patients and for the two
subgroups of patients planned with the two different age-specific target volumes.
Values of mean dose (Dmean) were similarly calculated. Finally, to quantify the variation in machine parameters
between patients’ treatment fields, we determined the minimum, maximum, and median
for the proton beam range, energy, and SOBP width for our population’s cranial and
spinal fields.

Results

Machine parameters for treatment delivery

Machine-specific treatment parameters for all 18 proton CSI treatment plans are summarized
in Table 2. As described in Methods, these values were automatically determined by the TPS on
the basis of the treatment-specific target contours. The variation in the proton beam
range, energy, and SOBP width within this population is largely attributed to the
wide interval in patient age and, thus, the wide interval in patient size. In general,
median values for range, energy, and SOBP width were higher for the cranial fields
than for the spinal fields. This difference is attributed to the larger axial size
of the cranial target than of the spinal target.

Table 2.Values for the minimum, maximum, median, and standard deviation (SD) across the population
(N = 18) for beam range (cm), energy (MeV) and width of the modulated range or spread
out Bragg peak (SOBP) (cm)

Dosimetric results

The DVHs and isodose distributions for two patients (patient 10 and 13) are shown
in Figures 5 and 6, respectively. These plans were was optimized to deliver mean doses between 103%
and 104% of the prescribed dose to the spinal cord and brain while dose to the eyes,
esophagus, and thyroid were reduced. Organs such as the lungs, kidneys, heart, and
liver were not specifically identified for dose reduction, but using the outlined
methodology, dose to these organs was minimized. The data for these two patients was
typical of our observations for the entire population of patients. That is that good
normal tissue sparing was achieved for all patients but normal tissue sparing was
better in the older patients when compared to the younger patients.

Figure 5.Dose volume histograms (DVH) for two representative patients with different age specific
target volumes. Solid lines are for patient 10: male, age 9 and dashed lines are for patient 13:
female, age 16.

Figure 6.Dose distributions for two representative patients with different age specific target
volumes. Panels on the left are for patient 13, female, age 16 and panels on right are for
patient 10: male, age 9. (a,e) Dose distribution in the axial plan at the level of the eyes. (b,g) Dose distribution in the axial plane, taken at the vertebral space between T8-T9
to show dose relative to the liver, heart, lungs, esophagus, and cord. (c,h) Dose distribution in the axial plane, taken at the vertebral space between L1-L2
to show dose relative to the liver, kidneys, and cord. (d,e) Dose distribution in the sagittal plane, taken at a poisiton lateral to the cord
to include aspects of the thyroid and esophagus in the image. (i) Isodose scale for images (a–h).

Organ-specific, population-averaged DVHs (for the 18 patients) are shown in Figure 7 for ten organs. In Table 3, population-averaged dose-volume results (Dmin, Dmax, and Dmean) for ten organs are reported separately for the entire patient population, and for
the two subgroups of patients, they are stratified according to the age-specific target
volumes. Overall, the standard deviations in the organ doses were lower for the subgroups
compared to the population as a whole (Table 3). The brain and spinal cord were part of the target volume and naturally had high
doses for all patients, with little difference in Dmin, Dmax, and Dmean observed between the entire population and subgroups. Additionally, our planning
technique produced similar results across the population of patents considered, as
evidenced by low standard deviations in the Dmin, Dmax, and Dmean values (Table 3) and the D5% through the D95% values (Figure 7) for the brain and spinal cord. For the remaining eight tissues considered, good
normal tissue sparing was achieved for all of the patients (Table 3, Figure 7). However, compared to the brain and spinal cord, there was larger standard deviation
in doses. This standard deviation was largely related the age specific target volumes
and to the proximity of the target volume to the organ. The eyes and the lenses received
higher doses than other organs. They are close to the cranial fields, and even with
optimization, dose could not be entirely eliminated by editing field-defining apertures
because of the finite penumbral width. Not surprisingly, the dose to the eyes and
brain were similar in all patients, including the patients with different age-specific
spinal target volumes because the cranial component of the target volume was the same
in all patients. The kidneys and lungs are both lateral to the spinal fields, and
therefore dose in these organs was dependent on the lateral margins assigned to the
spinal target volume, which varied with patient age and size. In the kidneys and lungs,
higher doses were observed for the patients whose target volume included CSF and vertebral
bodies compared to those whose target volumes only included CSF. The thyroid, liver,
heart, and esophagus are located distal to the spinal fields, and therefore dose in
these organs was largely governed by their proximity anteriorly to the target volume.
This distance was smaller in those patients whose spinal target volumes included the
entire vertebral bodies, and thus, doses to the thyroid, liver, heart, and esophagus
were higher for these patients compared to those whose target volumes only included
CSF. Of these organs, the heart, which was the most anterior, had the lowest mean
dose, whereas the esophagus, which was the most proximal, had the highest mean dose.

Table 3.The minimum, maximum, and mean dose values for the population (N = 18) in specific
organs of interest are listed along with the corresponding standard deviations (SD)

Discussion

In this study, we presented a standardized methodology for treatment planning for
passively-scattered proton CSI. To evaluate our planning methodology, we reviewed
individual treatment plans and organ-specific population-averaged DVHs (for the 18
patients) to quantitatively evaluate the consistency of plan quality across the population.
Furthermore, we examined differences in normal tissue doses related to age specific
target volumes by separately evaluating dosimetric parameters for the entire population
and the two target volume subgroups. We found that our standardized treatment planning
method yielded plans that were dosimetrically of high quality (i.e., generally satisfied
the dosimetric criteria in the Methods section) and dosimetrically consistent across
the population of 18 patients. For all patients, good normal tissue sparing was achieved,
but was better in the older patients whose target volumes only included CSF compared
to the younger patients whose target volumes included the CSF and entire vertebral
bodies.

In our evaluation of the planning technique, we focused on comparing dosimetric information
for the population in ten organs: lungs, liver, heart, kidneys, spinal cord, brain,
eyes, lenses, esophagus, and thyroid. The spinal cord, lenses, eyes, and thyroid were
specifically identified in the planning technique for optimization. Because the spinal
cord is located in the target volume, the goal of the planning method was to create
a homogeneous dose across the spinal cord without hot or cold spots (dose >105% or
<95% of the prescribed dose, respectively). Mean dose across the population of patients
was 2519.8 cGy (RBE) (107.6%) with a 1% SD, indicating high consistency in the planning
technique coverage, but because the mean dose was greater than 5% above the prescribed
dose, the dosimetric analysis revealed a potential trend toward plans with a higher
overall normalization. In the case of the eyes, the SD was 15%. Thus, there was relatively
low variation across the population even with patient-specific edits. In the case
of the thyroid, SD was high (141%), suggesting a potential need for improved standardization
of the optimization technique. However, because the mean organ dose was relatively
low (4.9 cGy (RBE)), the high SD may be a reflection of large variations of low dose.
Moreover an alternative method for reducing dose to the thyroid that maintains the
prescribed dose to the spinal cord is not known at this time.

One way that our proton CSI treatment technique could potentially be improved is through
modifications to our patient immobilization and set-up. While the immobilization technique
used at our institution for proton CSI achieves reproducible set-ups, it also results
in increased lateral penumbra of the proton treatment fields. Specifically the 10 cm
thick foam slab that is used to prevent the cranial fields from intercepting the treatment
couch creates a gap between the patient and the treatment couch which results in increased
lateral penumbra. The use of the foam slab was originally implemented several years
ago when we used a relatively dense table-top insert that was placed on the treatment
couch to facilitate indexing immobilization devices (MedTec, Kalona, IA, USA). At
the time the density of the table-top insert was not a concern because we were only
treating prostate cancer using lateral fields that did not intercept it. Later when
faced with the first proton CSI case at our institution, we were concerned about the
obliquely angled cranial fields traversing the high density indexed table-top insert.
Eventually, though minor modifications to the couches top extension, we were able
to index patients directly to the couch top extension and the indexing table top insert
was abandoned. Subsequently, we abandoned the use of compensators for the cranial
fields. With the removal of the indexing table-top insert, the removal of the compensator,
and the low density nature of the t couch top extensions, it is possible that elevating
of the patients with the 10 cm thick foam slab is no longer required. Reducing the
thickness or possible eliminating the foam slab all together may reduce the penumbra
somewhat. This would be particularly advantageous for reducing dose to the eyes and
lenses. However, moving forward, we will need to carefully consider changes to patient
set-up and immobilization prior to implementing any changes. Nonetheless, our experience
may be useful for other institutions as they select their treatment couches and immobilization
devices; table tops should be low density and allow immobilization devices to be easily
indexed. Also, gaps between the treatment couch and patient should be minimized where
possible.

While there is a great need for studies which compare proton treatments between institutions
and with photon therapy, to date there are only a few reports in the literature that
compare photon CSI and passively scattered proton CSI. Furthermore, it is difficult
to fully interpret the results of these studies because none have provided a detailed
description of the proton planning techniques that were used. In particular, Yuh et
al. [10] reported on the toxicity of 3 pediatric patients (3–4 years of age) after CSI with
protons, St Clair et al. [7] performed planning study of the comparative normal tissue sparing following conventional
photon CSI, IMRT, and passively scattered proton CSI for 1 patient (aged 43 months),
Yoon et al. [9] performed a dosimetric comparison of CSI using tomotherapy vs. passively scattered
protons for 10 patients (mean age 7 years), Miralbell et al. [38] compared risk of second cancers following proton, conventional photon therapy, and
IMRT in a 3 year old boy for spinal irradiation (cranial fields not considered), Newhauser
et al. [39] compared the risk of second cancers from CSI using passively scattered proton, intensity
modulated proton, conventional photon, and IMRT in a 3 year old boy, Taddei et al.
[8] considered the risk of second cancers following CSI with passively scattered protons
in a male patient (age 10) versus a female patient (age 9). The proton treatment planning
techniques that were used in several of those studies (Table 4) indicate that the methodology for passively scattered proton CSI has varied considerably
between studies. Specifically, reported methodologies vary in almost all regards from
the orientation of the cranial fields to the definition of the uncertainty margins.
Of particular note is that there is no specific mention of how the plans were optimized
for patient-specific anatomies, i.e., there is little agreement for uncertainty margins
used in the different studies, and there is no explanation of how uncertainty margins
were selected. Thus, there is a substantial potential for differences in dosimetric
results between studies, and this makes direct comparison of the dosimetric results
difficult. Nonetheless our dosimetric results are in reasonably good agreement with
previous investigations of proton CSI, including [7-10,32,38,39].

The problem of inter-institutional variations in planning for proton CSI, including
variability in target volume definitions, specifically with respect to uncertainty
margins and dose constraints has been noted before [5]. Nonetheless, proton therapy is in evolution, and as the evolution progresses, the
need for standardized, or at minimum documented and reproducible, planning methods
increases [5]. A standardized methodology is clearly essential for robust dosimetric comparisons
between centers and treatment modalities, and such comparisons are integral to progress
in the area of randomized trials. In the interim, there is potential for comparative
in silico studies, especially for populations (such as pediatric populations) too small for
randomized trials. However, even in silico trials require a standardized planning methodology because dose distributions across
tumor and normal tissues are compared, and from these, conclusions are drawn about
the general effects of proton therapy relative to photon therapy as in the studies
of Yoon et al. [9] and St. Clair et al. [7]). Nonetheless, progress is being made toward actual randomized trials. For example,
in a recent work, Howell et al. [31] performed a dosimetric comparison using an actual patient population and the standardized
treatment planning methodology outlined here, and they found that proton CSI improved
normal tissue sparing while also providing more homogeneous target coverage than photon
CSI. Thus, the potential for similar studies is growing, and with increased standardization,
the evidence from these studies is becoming increasingly robust.

Conclusions

This study described and evaluated a standardized method for proton treatment planning
for CSI. Overall, the standardized planning methodology yielded consistently high
quality treatment plans and perhaps most importantly, it did so for an anatomically
diverse patient population without creating outliers. Finally, the planning methodology
described here can be used to provide guidance to other proton centers as they implement
CSI.

Consent

Written informed consent was obtained from the patient for publication of this report
and any accompanying images.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

AG created the proton treatment plans, performed data analysis, and drafted the manuscript.
WN supervised retrospective collection of patient data, reviewed data analyses, and
edited the manuscript. RA provided guidance on clinical aspects of the manuscript,
particularly those pertaining to patient set-up and field definition, and edited the
manuscript. AM provided guidance on all clinical aspects of this manuscript, reviewed
and approved each proton treatment plan, and edited the manuscript. KH reviewed/edited
the manuscript and participated in various aspects of data analysis including writing
an excel macro to process the Eclipse DVHs and extract specified dosimetric parameters.
RH designed this study, provided scientific leadership to the research team, mentored
AG in the writing the manuscript, reviewed data analyses, reviewed/edited all drafts
of the manuscript, and prepared the revised manuscript and responded to reviewer comments.
All authors read and approved the final manuscript.

Acknowledgments

We acknowledge Ms. Kathryn Carnes for assistance in editing this manuscript. This
research was supported in part, by a cancer prevention fellowship supported by the
National Cancer Institute through grant R25T CA57730, Shine Chang, Ph.D., Principal
Investigator; by the National Cancer Institute award 1R01CA131463-01A1 (W.D. Newhauser,
Ph.D., P.I.) and a subcontract of that award (R.M. Howell, Ph.D., P.I); and by Northern
Illinois University through a subcontract of the US Department of Defense (award W81XWH-08-1-0205,
J. Lewis, Ph.D., P.I.; W D. Newhauser, Ph.D., P.I. of subcontract).